Today, anticoagulants are widely used to prevent and treat a variety of thromboembolic events. Currently, available anticoagulants for treatment include unfractionated heparin (UFH), low molecular weight heparin (LMWH), and vitamin K antagonists (VKAs) (e.g., warfarin). More recently, synthetic pentasaccharides (e.g., fondaparinux (Arixtra®)) have also been developed as effective anticoagulants. The advantage of fondaparinux over LMWH or UFH is that the risk for heparin-induced thrombocytopenia is substantially reduced as fondaparinux inhibits factor Xa via binding to antithrombin III and does not inhibit thrombin or possess other activities of heparin.
Although anticoagulants are effective in treating and reducing the risk of thromboembolic disease, they are associated with significant drawbacks that limit their use and acceptability in the clinical setting. The traditional anticoagulants are administered parenterally and require frequent monitoring and subsequent dose adjustment. For example, UFH, LMWH, and fondaparinux are administered parenterally, which is inconvenient and expensive for long-term use, particularly outside of the hospital setting where visits to or from a health care professional may be required. Vitamin K antagonists are the only available oral anticoagulants. However, they usually have a narrow therapeutic window and unpredictable pharmacology, and require close monitoring and dose adjustment to ensure that anticoagulant effects remain within the therapeutic range.
Different approaches have been proposed to develop orally administered anticoagulants. One approach is to develop small molecule direct factor Xa inhibitors. Unlike the more traditional anticoagulants (UFH, LMWH, and VKAs) that target multiple enzymes in the coagulation cascade, the new drugs inhibit single enzymes. Currently, several oral factor Xa inhibitors are in clinical development, such as rivaroxaban (Bayer HealthCare AG and Scios, Inc.), apixaban (Bristol-Myers Squibb), and 813893 (GlaxoSmithKline).
Despite the recent promising development of direct factor Xa inhibitors, there is a continuing need for development of novel pharmaceutical formulations of selective factor Xa inhibitors suitable for oral administration, which not only offer the convenience of oral dosing, but also provide a reproducible and predictable bioavailability of the active ingredient.